Abstract
Monocytes/macrophages are a diverse group of cells that act as first responders in innate immunity and then as mediators for adaptive immunity to help clear infections. In performing these functions, however, the macrophage inflammatory responses can also contribute to pathogenesis. Various monocyte and tissue macrophage subsets have been associated with inflammatory disorders and tissue pathogeneses such as occur during HIV infection. Non-human primate research of simian immunodeficiency virus (SIV) has been invaluable in better understanding the pathogenesis of HIV infection. The question of HIV/SIV-infected macrophages serving as a viral reservoir has become significant for achieving a cure. In the rhesus macaque model, SIV-infected macrophages have been shown to promote pathogenesis in several tissues resulting in cardiovascular, metabolic, and neurological diseases. Results from human studies illustrated that alveolar macrophages could be an important HIV reservoir and humanized myeloid-only mice supported productive HIV infection and viral persistence in macrophages during ART treatment. Depletion of CD4+ T cells is considered the primary cause for terminal progression, but it was reported that increasing monocyte turnover was a significantly better predictor in SIV-infected adult macaques. Notably, pediatric cases of HIV/SIV exhibit faster and more severe disease progression than adults, yet neonates have fewer target T cells and generally lack the hallmark CD4+ T cell depletion typical of adult infections. Current data show that the baseline blood monocyte turnover rate was significantly higher in neonatal macaques compared to adults and this remained high with disease progression. In this review, we discuss recent data exploring the contribution of monocytes and macrophages to HIV/SIV infection and progression. Furthermore, we highlight the need to further investigate their role in pediatric cases of infection.
Highlights
A cure for human immunodeficiency virus (HIV) infection continues to be elusive, despite the use of antiretroviral therapy (ART)
Our interpretation is that the increased monocyte turnover was due to a compensatory mechanism to replace the short-lived macrophages (IM), which were destroyed by simian immunodeficiency virus (SIV) in the tissues. This increase in turnover of both monocytes and interstitial macrophages (IM) corresponds to greater infection of long-lived alveolar macrophages (AM), mechanisms for this relationship are unclear. Based on these studies we proposed a working model as shown in Figure 4 that (a) There exist at least two types of macrophages in the lung including the shorter-lived IM exhibiting relatively higher turnover during homeostasis suggesting a critical role for daily protection, and longer-lived AM that exhibit lower turnover rate; (b) Increased SIV infection of both IM and AM correlates with acquired immune deficiency syndrome (AIDS) disease progression; (c) SIV-induced IM apoptosis promotes further increases in IM turnover rate in contrast to AM that become infected with SIV but exhibit far lower rates of apoptosis and turnover
This could be due to the shorter half-lives of some macrophage subsets, small sample sizes, and/or threshold detection limitations in assays employed for detecting virus
Summary
A cure for HIV infection continues to be elusive, despite the use of antiretroviral therapy (ART). Declining numbers of CD4+ T cells during HIV/SIV infections have long been attributed as the primary cause of Macrophages and HIV/SIV Pathogenesis immune-deficiency, progression to acquired immune deficiency syndrome (AIDS), and sites of virus reservoirs established during ART. While it is likely that various other immune cells influence disease progression and viral seeding, the purpose of this review is to focus on the contribution of monocytes and macrophages to HIV/SIV infection. Monocyte levels in blood remain constant during infection, the monocyte turnover rate increases during the onset of simian AIDS (SAIDS) and reflects damage to short-lived tissue macrophages. Physiological monocyte turnover rate in neonates (
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